Rates of serotonin synthesis were measured in the human brain using positron emission tomography. The sensitivity of the method is indicated by the fact that measurements are possible even after a substantial lowering of synthesis induced by acute tryptophan depletion. Unlike serotonin levels in human brain, which vary greatly in different brain areas, rates of synthesis of the indolamine are rather uniform throughout the brain. The mean rate of synthesis in normal males was found to be 52% higher than in normal females; this marked difference may be a factor relevant to the lower incidence of major unipolar depression in males.

https://www.pnas.org/content/pnas/94/10/5308.full.pdf

Differences between males and females in rates of serotonin synthesis in human brain.

Nonhuman primates offer unique opportunities to study the effects of genes, environments, and their interaction, on physiology and complex behavior. We examined genotype and early environment contributions to CNS function in a large sample of rhesus monkeys. In humans, length variation of the serotonin (5-HT) transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) that results in allelic variation in 5-HTT expression is associated with decreased serotonergic function and 5-HT-mediated psychopathology. We report that an analogous variation of the gene's regulatory region in monkeys interacts with early experience to affect central 5-HT functioning. Monkeys with deleterious early rearing experiences were differentiated by genotype in cerebrospinal fluid concentrations of the 5-HT metabolite, 5-hydroxyindoleacetic acid, while monkeys reared normally were not. These findings demonstrate an environment-dependent effect of the rh5-HTTLPR genotype on CNS 5-HT function and suggest nonhuman primates may provide an important avenue for investigating gene/environment interactions using candidate genes for physiological and behavioral traits.

Early experience and serotonin transporter gene variation interact to influence primate CNS function.

Genetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders?

Imaging genetics: perspectives from studies of genetically driven variation in serotonin function and corticolimbic affective processing.

OBJECTIVE: Abnormalities in dopamine neurotransmission in the prefrontal cortex have been implicated in the pathophysiology of schizophrenia. However, the integrity of the dopamine projections to the prefrontal cortex in this disorder has not been directly examined. METHOD: The authors employed immunocytochemical methods and antibodies against tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis, and the dopamine membrane transporter to examine dopamine axons in the dorsomedial prefrontal cortex (area 9) from 16 pairs of schizophrenic and matched control subjects. RESULTS: Compared to the control subjects, the total length of tyrosine hydroxylase-immunoreactive axons was unchanged in the superficial and middle layers of the schizophrenic subjects but was reduced by an average of 33.6% in layer 6. The total length of tyrosine hydroxylase-positive axons in layer 6 was decreased in 13 of the schizophrenic subjects compared to their control subjects. Axons immunoreactive for the dopamine me...

https://ajp.psychiatryonline.org/doi/pdf/10.1176/ajp.156.10.1580

Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects.

Serotonin2 receptors and the serotonin transporter in the schizophrenic brain

[3H]Paroxetine binding to particulate membrane from tissue, obtained at autopsy, from the hippocampus, frontal cortex, and caudate nucleus from subjects who had or had not had schizophrenia was measured. The density of [3H]paroxetine binding to membranes from subjects who had or had not had schizophrenia did not differ. Similarly, the affinity of [3H]paroxetine binding in the frontal cortex and caudate nucleus was not different. By contrast, the affinity of [3H]paroxetine binding to hippocampal membrane from subjects who had schizophrenia was significantly lower than the affinity of binding for the nonschizophrenic subjects (0.40 +/- 0.06 vs. 0.26 +/- 0.02; p < 0.05). As [3H]paroxetine binds to the serotonin transporter, these data suggest that the serotonin transporter is altered in the hippocampus in subjects with schizophrenia.

[3H]paroxetine binding is altered in the hippocampus but not the frontal cortex or caudate nucleus from subjects with schizophrenia.

Allelic association case-control analysis of a deletion/insertion polymorphism in the serotonin transporter-linked polymorphic region (5-HTTLPR) has suggested associations with unipolar disorder, bipolar disorder, depression, and Alzheimer’s disease Moreover, the heterozygous long form of the 5-HTTLPR has been associated with increased levels of mRNA for the serotonin transporter (5-HTT) and increased serotonin uptake in lymphoblastic cell lines This study attempts to determine whether there is an association between 5-HTTLPR genotype and schizophrenia or the binding of [3H]paroxetine to the human hippocampal 5-HTT DNA from the cerebellum from 58 schizophrenic and 62 control subjects was used to genotype the 5-HTTLPR In addition, the relationship between 5-HTTLPR genotype and the affinity and density of [3H]paroxetine binding to the hippocampal 5-HTT was assessed There were no associations between 5-HTTLPR allotype or genotype and/or the parameters of [3H]paroxetine binding to the hippocampal 5-HTT Our data suggest that 5-HTTLPR genotype neither confers an increased susceptibility for schizophrenia nor dictates the expression of the 5-HTT in the human hippocampus

/pdf/no-association-between-the-serotonin-transporter-linked-2515s79d50.pdf

No association between the serotonin transporter-linked promoter region polymorphism and either schizophrenia or density of the serotonin transporter in human hippocampus.

[3H]paroxetine binding to membrane from hippocampus, obtained at autopsy, from 24 schizophrenic and 24 non-schizophrenic subjects has been measured. The affinity of [3H]paroxetine binding to hippocampal membrane was decreased in subjects with schizophrenia (Kd=0.50 ± 0.04 vs. 0.24 ± 0.02nM; mean ± S.E.M. p < 0.001) but was not different in schizophrenic subjects who had or had not committed suicide (Kd=0.50 ± 0.07 vs. 0.50 ± 0.04nM). The density of [3H]paroxetine binding sites did not differ between the schizophrenic and non-schizophrenic subjects. For the schizophrenic subjects, there was no relationship between ante-mortem neuroleptic drug treatment and [3H]paroxetine binding to the hippocampal membrane. Finally, this study has shown that neuroleptic drug treatment of rats does not alter [3H]paroxetine binding to the hippocampal membranes. Thus, it would seem that the changes in the affinity of [3H]paroxetine binding to the hippocampus of schizophrenic subjects are not likely to be due to neuroleptic drug treatment but may be involved in the pathology of the illness.

Lee Naylor

Papers

Serotonin2 receptors and the serotonin transporter in the schizophrenic brain

[3H]paroxetine binding is altered in the hippocampus but not the frontal cortex or caudate nucleus from subjects with schizophrenia.

No association between the serotonin transporter-linked promoter region polymorphism and either schizophrenia or density of the serotonin transporter in human hippocampus.

Changes in the serotonin transporter in the hippocampus of subjects with schizophrenia identified using [3H]paroxetine

Altered hippocampal [3H]paroxetine binding in subjects with schizophrenia